The goals of the proposed training program are two-fold: (i) to provide training and mentoring to prepare Dr. Brillantes for an independent research career in diabetes/beta cell biology and (ii) to identify physiologically and functionally relevant cellular and molecular mechanisms employed by pancreatic beta cells to adapt to hyperglycemia and insulin demands. To date, downstream beta cell-specific transcripts for glucose stimulated signaling pathways controlling beta cell growth, replication and survival remain largely unknown. By exploiting the divergent beta cell phenotypes of the diabetes susceptible C57BLKS/J (KS) mice and the diabetes resistant C57BL6/J (B6) mice in response to hyperglycemia, the trainee proposes to identify functionally relevant beta cell genes and signaling pathways involved in the control of compensatory beta cell mass. The trainee hypothesizes that distinct beta cell adaptive phenotypes characterizing these two inbred mouse strains are mediated by allelic differences that result in the discordant regulation of beta cell specific gene transcripts in response to glucose-stimulation. In Aim 1, she will characterize the relative contributions of cellular processes (islet neogenesis, beta cell hypertrophy, beta cell replication, beta cell apoptosis) controlling beta cell mass in obese B6 and obese KS mice to guide vetting of candidate genes identified in Aim 2. In Aim 2, she will generate a list of candidate molecules associated with the success or failure of beta cell adaptation to excess glucose stimulation by using massive parallel analysis of gene expression in pancreatic islets of B6 and KS mice. She will narrow the selection of candidate genes by virtue of their discordant regulation in response to hyperglycemia between the two strains, their position in divergent areas of the B6 and KS genome, and their consistent regulation across several experimental models of hyperglycemia. In Aim 3, she will further analyze candidate genes using in vitro islet expression studies to identify genes whose altered expression can mediate predicted changes in beta cell replication or apoptosis. Finally, candidate genes that meet the above selection criteria and show functional relevance to beta cell mass will then be further prioritized by virtue of their predicted functions and sequence variations between the B6 and KS strain for use in transgenic mouse experiments. Generation of transgenic mice will be designed to block beta cell expansion in obese B6 mice or "rescue" the failing islets in obese KS mice. The proposed experiments are designed to identify beta cell-specific genes that affect the capacity of beta cells to survive in the setting of increased glycemic stress. Such insights could lead to a fundamental understanding of beta cell viability in hyperglycemic environments from which medical therapies directed towards the primary prevention, treatment or cure for diabetes are based. The research activities and formal course work in relevant fields of genetics, cell biology, transgenics, and bioinformatics will enable an independent research career for Dr. Brillantes.